We currently have a limited understanding of how prostate cancer progresses from a localized, treatable disease to a disseminated incurable one. Our long term goal is to understand the biological mechanisms underlying prostate cancer progression and metastasis in order to improve diagnosis and treatment of this disease. One mechanism that has been implicated in prostate cancer progression is alteration of cellular interactions with the extracellular matrix (ECM). We have been focusing on the role of dystroglycan (DG) a cellular receptor for ECM proteins in this process. DG has been shown to be involved in the development and function of normal epithelia and its expression is reduced or eliminated in advanced carcinomas, including prostate cancer. It is also known that appropriate carbohydrate modification of the extracellular portion of DG, which is in part mediated by the LARGE protein, is necessary for its ability to bind its ECM ligands, and we show here that this is disrupted in human prostate cancer cell lines and clinical specimens. However, the consequences of this for disease progression and whether this can distinguish aggressive from indolent cases is not yet known. Based on our preliminary data, we hypothesize that inappropriate glycosylation of DG results in structural and functional perturbations of the ECM that contribute to prostate cancer progression. Here we have brought together a combination of cell-based assays, animal models of prostate cancer, and evaluation of clinical specimens to address this hypothesis with the following specific aims: 1) Evaluate cause of ?DG hypo-glycosylation and its effects on prostate cancer progression;2) Determine the effects of loss of DG function on tumor progression and metastasis in a mouse model of prostate cancer;3) Determine the prognostic significance of ?DG glycosylation status and LARGE expression in human prostate cancer. The successful completion of these studies will define a novel pathogenic mechanism and disease biomarker underlying prostate cancer progression. PUBLIC HEALTH RELEVANCE: Understanding the biological mechanisms driving prostate cancer progression is essential for developing new ways to treat and diagnose this disease. In this proposal, we are focusing on how dystroglycan, a receptor for extracellular matrix proteins, is involved in this process.